Abstract 3851: Microenvironmental alterations co-occur with mosaic somatic clonal expansions in normal tissues
Authors: Chetan Munugala, Jieting Hu, Eirini Christodoulou, Venkata Yellapantula
Journal: Cancer Research (2022)

Abstract Clonal hematopoiesis confers an increased risk for myeloid neoplasia, but progression to cancer requires additional alterations. Recently described clonal expansion (CE) of mutant skin and esophagus suggests CE is pervasive across tissues. Immune evasion and angiogenesis, reliant on the microenvironment (ME), are cancer hallmarks, yet ME changes in the setting of CE have not been systematically studied. Using GTEX RNA-Seq data (25 normal tissues, n = 6,511), previously reported somatic variants (Yizhak K, Science 2019) and normalized gene expression values were downloaded. Samples were grouped by the presence of: non-synonymous mutation (NSM) in a COSMIC Cancer Gene Census gene (CGC-m), NSM in a non-cancer gene or no NSM (non-m). ME scores, i.e. stromal and immune cell abundances for all samples, were estimated using Xcell and CIBERSORTx. Our analyses focused on tissues with at least 10 CGC-m, especially skin and esophagus which had the most CGC-m cases (77/600, 12% and 166/512, 32% respectively; median :4.6%). We also compared ME scores from skin and esophagus with corresponding cancer data from TCGA. Differential gene expression (DEG) testing between CGC-m and non-m samples, Gene Set Enrichment Analysis (GSEA), and hypoxia scores (Bhandari V, Nature Comm 2020) based on findings (below) were generated. ME scores significantly differed in the CGC-m vs. non-m cohorts, with increased epithelial and lymphatic endothelial cells (skin, esophagus), megakaryocytes (skin, prostate) and neutrophils (prostate, lung) (Wilcoxon FDR p-value &amp;lt; 0.01). Skin showed reduced fibroblasts and esophagus, increased endothelial cells and melanocytes and lower pericytes and erythrocytes. Comparing TCGA and GTEX data, melanoma showed similar but more marked epithelial cell increase and fibroblast reduction. Esophageal carcinoma showed similar but more pronounced reductions in pericytes and erythrocytes. DEG testing between CGC-m and non-m identified: in esophagus, overexpression of genes aberrant in carcinomas (ERBB2, CDH1, SOX2 and TP63; p-adjusted &amp;lt; 0.01), downregulation of pro-angiogenic factors and those involved in pericyte recruitment (FGF2, ANGPT1 and PDGFB); in skin, extracellular matrix protein, ELN was overexpressed. GSEA analysis of differentially expressed genes identified dysregulation of mesenchymal-epithelial transition and myogenesis pathways in both tissues and angiogenesis-related pathway in esophagus. Hypoxia scores were markedly higher in CGC-m vs. non-m esophagus samples (Wilcoxon FDR p-value &amp;lt; 0.01). These results suggest ME alterations participate in initial stages of cancer progression and are tissue-specific. High hypoxia scores support a hypothesis of its early initiating role in CE-related angiogenesis in esophagus. Studying these changes may reveal novel avenues for early cancer intervention, immune or other targeted therapies and enhancement of conventional therapies. Citation Format: Chetan Munugala, Jieting Hu, Eirini Christodoulou, Venkata Yellapantula. Microenvironmental alterations co-occur with mosaic somatic clonal expansions in normal tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3851.